“It is clear that FDA wants to move forward with biosimilar approvals and they will be looking to a totality of the evidence as the standard for a determination of biosimilarity.”

He also commented that FDA wants a constant dialog with biosimilar sponsors and all the structural and functional data up front. “Their goal for the up-front data is to be involved in design of the clinical trials in order to maximize the data provided.”

FDA’s new documents describe a step-wise approval pathway, starting with extensive analytical, physicochemical, and biological characterization data that will have to demonstrate a high degree of similarity to the reference product. FDA will evaluate that data and then provide advice to the sponsor on the extent and scope of animal and human testing needed to show biosimilarity.

The agency will consider multiple factors in making study determinations, including product complexity, formulation, stability, structure-function relationships, manufacturing process, and clinical experience with the reference product.

While the pathway to the agency’s decision making will be abbreviated, “it will depend on existing data,” Rachel Sherman, M.D., director of the Office of Medical Policy in FDA’s Center for Drug Evaluation and Research, said during a conference call.

“We do not want companies repeating studies that do not need to be done.” As to whether most biosimilar applicants will be expected to carry out clinical trials, decisions will be made on a product by product basis.

Another topic of note is that the FDA has said that there could be extrapolation of clinical data to other diseases to give companies developing biosimilars approval for use in multiple indications for a given product. “But for therapeutics like Rituxan with two disparate indications, one for lymphoma and another for rheumatoid arthiritis, two sets of clinical trials will likely be required,” Dr. Calvo explained.

Interchangeability and Exclusivity

Importantly for the industry, the guidance documents indicate that the agency hasn’t settled some important biosimilars policy questions, including requirements for demonstrating interchangeability of a biosimilar with a reference product and terms for establishing the exclusivity period for pioneer biologics.

The Patient Protection and Affordable Care Act, signed into law by President Barack Obama on March 23, 2010, mandated the creation of an abbreviated approval pathway for biosimilars and proposed a 12-year data exclusivity period. The president’s budget proposal for fiscal 2013 released February 13, however, suggests that exclusivity should be lowered to seven years.

With regard to interchangeability, FDA states that it “is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product.” Dr. Calvo explained that “interchangeability is important because it provides for a period of market exclusivity as well for automatic substitution of the interchangeable for the approved biologic without intervention from the prescribing physician.”

“However,” Dr. Calvo added, “given how new the whole process for biosimilar approval is, it would have been surprising if the FDA would have said there would not be any issues in determining interchangeability.” But, he noted, the agency has said that right now it doesn’t have the scientific ability to approve biosimilars as interchangeable.

An Amgen spokesperson commented that “FDA’s acknowledgement that determining interchangeability is scientifically difficult at this time is important. Patient safety does not stop at approval, and Amgen believes that post-approval activities including ongoing monitoring are essential to patient safety.”

Dr. Sherman believes that the hurdles for interchangeability would be high. Biologic drugs carry the added risk of prompting an immune response, she noted, and the FDA would “almost certainly” require clinical trials in which a patient is switched from the branded drug to the biosimilar and back to rule out the risk of triggering the immune system.

Potential Cost Savings

Dr. Calvo pointed out that “the ability to have a high level of FDA input will likely increase the chance that biosimilars will soon enter the U.S. market.” However, he added, the price erosion that occurs with small molecules “will not happen for biosimilars to even close to the extent that it occurs with small molecules, mainly because there will not be a mechanism for automatic substitution and because clinical studies will be required at least to some degree.”

For more complex products such as antibody conjugates or highly purified protein mixtures, “it is highly likely that more sophisticated manufacturing and analytical methods and possibly clinical trials will be required, therefore increasing costs for biosimilar entrants,” Jefferies analyst Biren Amin said in a note to clients.

The Congressional Budget Office still estimates that biosimilars would save the government $25 billion in healthcare spending during the coming decade. While generic chemical compounds like Norvasc and Metoprolol usually sell for less than 20% the cost of the brand product, biosimilars are expected to sell for 60% to 80% of the cost of branded biologics. The difficulty of producing and gaining approval for biosimilars will provide manufacturers increased pricing power and larger margins compared to traditional generic medications.

Biosimilars represent a tremendous opportunity for pharma and biotech companies that can successfully manufacture and market them. The global market for biosimilars will range between $11 billion and $25 billion by 2020, accounting for 4 to 10 percent of the total market for biotech drugs, according to IMS Health.

Despite the potential hurdles to both interchangeability and exclusivity, patent expiries in the next two years put around $11 billion in biologic drug sales into play. That kind of potential along with the establishment of a designated approval pathway clears away some lingering doubts about the viability of generic competition.

As for the industry, potential biosimilar manufacturers continue to make deals. While there are no currently marketed biosimilars in the U.S., so-called innovator companies have joined the ranks of generic firms in developing biosimilars.

Amgen told GEN that as a provider of biologic medicines, it understands the challenges of developing and manufacturing innovative and biosimilar medicines and appreciates the agency’s efforts on the guidelines, and encourages adoption of a thorough review and approval process.

While it remains to be seen whether approved biosimilars provide the savings in healthcare costs that the Congressional Budget Office optimistically predicted, both the FDA and the industry are moving toward making them a reality in the U.S.

As per the three dozen or so requests for meetings, FDA staffers are holding pre-IND meetings with sponsors and encouraging all prospective biosimilar makers to seek early advice. Nine INDs for biosimilar have been filed so far.

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